Different Group A Streptococcus pili lead to varying proinflammatory cytokine responses and virulence.

The human pathogen Streptococcus pyogenes, or Group A Streptococcus (GAS), is associated with a variety of diseases ranging from mild skin and soft tissue infections to invasive diseases and immune sequelae such as rheumatic heart disease. We have recently reported that one of the virulence factors of this pathogen, the pilus, has inflammatory properties and strongly stimulates the innate immune system. Here we used a range of nonpathogenic Lactococcus lactis gain-of-function mutants, each expressing one of the major pilus types of GAS, to compare the immune responses generated by various types of fully assembled pili. In vitro assays indicated variability in the inflammatory response induced by different pili, with the fibronectin-binding, collagen-binding, T antigen (FCT)-1-type pilus from GAS serotype M6/T6 inducing significantly stronger cytokine secretion than other pili. Furthermore, we established that the same trend of pili-mediated immune response could be modeled in Galleria mellonella larvae, which possess a similar innate immune system to vertebrates. Counterintuitively, across the panel of pili types examined in this study, we observed a negative correlation between the intensity of the immune response demonstrated in our experiments and the disease severity observed clinically in the GAS strains associated with each pilus type. This observation suggests that pili-mediated inflammation is more likely to promote bacterial clearance instead of causing disruptive damages that intensify pathogenesis. This also indicates that pili may not be the main contributor to the inflammatory symptoms seen in GAS diseases. Rather, the immune-potentiating properties of the pilus components could potentially be exploited as a vaccine adjuvant.

Intra- and Post-procedural Patient-reported Experience Measures and their Correlation with post-ERCP Adverse Events and Unplanned Healthcare Utilization.

Background and Study Aims Post-endoscopic retrograde cholangiopancreatography (ERCP) adverse events (AEs) are common, as is unplanned healthcare utilization (UHU). We aimed to elucidate potential associations between intra- and post-procedural patient-reported experience measures (PREMs) and post-ERCP AEs and UHU. Patients and Methods Prospective data from a multi-center collaborative were used. A validated 0-10 Likert-based PREM assessing intra- and post-procedural symptoms was applied to patients following ERCP and protocolized follow-up was performed at 30 days to identify AEs and UHU for reasons not meeting the definitions of any AE. Multivariable logistic regression was conducted using PREM domains as exposures and individual AEs and UHU as outcomes, with a priori selected patient- and procedure-related covariates. Test performance characteristics and odds ratios (ORs) and 95% confidence intervals (95% CIs) for each PREM domain were reported. Results From September 2018 through October 2023, 3,434 ERCPs were included. Post-procedural abdominal pain of >3 was predictive of pancreatitis (OR 3.71, 2.37-5.73), while a score >6 was strongly predictive of perforation (OR 9.54, 1.10-59.37). Post-procedural pain was also predictive of UHU within 30 days when used as a continuous predictor (OR 1.08 per point, 1.01-1.16). Post-procedural pain of >6 demonstrated high negative predictive values and specificities for post-ERCP AEs. Conclusions Patient-reported symptom scores from a simple Likert-based PREM at the time of discharge from ERCP are associated with presentations for pancreatitis, perforation, and UHU within 30 days. Applying PREMs post-ERCP could potentially prevent UHU and/or facilitate earlier management and improved outcomes for patients with post-ERCP AEs.

Collaborative international partnership: Enabling the development of a state-of-the-art minimally invasive surgical center in rural Uganda through telementoring.

BACKGROUND: Access to minimally invasive surgery (MIS) is limited in Sub-Saharan African countries. In 2019, the Mount Sinai Department of Surgery in New York collaborated with local Ugandans to construct the Kyabirwa Surgical Center (KSC), an independent, replicable, self-sustaining ambulatory surgical center in Uganda. We developed a focused MIS training program using a combination of in-person training and supervised telementoring. We present the results of our initial MIS telementoring experience. METHODS: We worked jointly with Ugandan staff to construct the KSC in the rural province of Jinja. A solar-powered backup battery system ensured continuous power availability. Underground fiber optic cables were installed to provide stable high-speed Internet. The local Ugandan general surgeon (JOD) underwent a mini-fellowship in MIS and then trained extensively using the Fundamentals of Laparoscopic Surgery program. After a weeklong in-person session to train the Ugandan OR team, JOD performed laparoscopic cases with telementoring, which was conducted remotely by surgeons in New York via audiovisual feeds from the KSC OR. RESULTS: From October 2021 to February 2024, JOD performed 61 telementored laparoscopic operations at KSC including 37 appendectomies and 24 cholecystectomies. Feedback was provided regarding patient positioning, port placement, surgical technique, instrument use, and critical steps of the operation. There were no intra-operative complications. Postoperatively, field medical workers visited patients at home to collect follow-up information. Two superficial wound infections (3.3%) were reported in the short-term follow-up. CONCLUSION: Telementoring can be safely implemented to assist surgeons in previously underserved areas to provide advanced laparoscopic surgical care to the local patient population.

Expanding strain coverage of a group A Streptococcus pilus-expressing Lactococcus lactis mucosal vaccine.

Group A Streptococcus (GAS) is a human pathogenic bacterium that can trigger a wide range of diseases, including the autoimmune diseases acute rheumatic fever and rheumatic heart disease, causing major morbidity and mortality in many low- and middle-income countries. Primary intervention programs have had limited success thus far, and a licensed vaccine has yet to be developed. The pilus of GAS is known to be involved in host cell adhesion, biofilm formation and immune evasion. We have a mucosal vaccine in development that expresses the pilus of GAS on the surface of the nonpathogenic bacterium Lactococcus lactis. To expand strain coverage, we combined seven L. lactis constructs, each expressing a different GAS pilus variant, and investigated the systemic and mucosal immune responses following immunization. Mice immunized with this combination showed specific immunoglobin G and immunoglobin A responses to the GAS pilus proteins of vaccine strains, at levels comparable to mice immunized with a single construct. Cross-reactivity to pilus proteins of nonvaccine strains was also evident. Furthermore, protective efficacy against a homologous strain of GAS in a murine nasopharyngeal colonization model was observed. Overall, this study provides further evidence for using pilus-expressing lactic acid bacteria as a vaccine to prevent upper respiratory tract GAS infections.

REMIT-UC: Real-World Effectiveness and Safety of Tofacitinib for Moderate-to-Severely Active Ulcerative Colitis: A Canadian IBD Research Consortium Multicenter National Cohort Study.

INTRODUCTION: We aimed to evaluate the real-world effectiveness and safety of tofacitinib for the treatment of ulcerative colitis (UC). METHODS: REMIT-UC is a Canadian multicenter cohort study. Standardized data collection was performed on 334 consecutive adult outpatients with UC treated with tofacitinib. The primary outcomes were achievement of clinical and endoscopic remission. Safety outcomes were reported using incidence rates (events/100 patient-years of exposure). A multivariable Cox proportional hazards model was used to evaluate predictors of loss of response after tofacitinib dose de-escalation to 5 mg twice daily (BID). RESULTS: Clinical remission was achieved by 35.3% (106/300), 36.0% (104/289), and 35.2% (93/264) of patients at weeks 12, 24, and 52, respectively. Endoscopic remission was achieved by 18.5% (15/81), 23.0% (28/122), and 25.7% (35/136) of patients at weeks 12, 24, and 52, respectively. Incidence of serious infections, herpes zoster, and venous thromboembolism were 2.1 [0.9-4.2], 0.5 [0.1-1.9], and 1.1 [0.3-2.7], respectively. Among responders, 44.5% (109/245) lost response during follow-up, which was recaptured in 54.9% (39/71) of patients who re-escalated to 10 mg BID. Patients with a baseline Mayo endoscopic score of 3 (adjusted hazard ratio 3.60 [95% confidence interval: 1.70-7.62]) and prior biologic failure (adjusted hazard ratio 3.89 [95% confidence interval: 1.28-11.86]) were at a higher risk for losing response after dose reduction. DISCUSSION: One-third of patients with UC treated with tofacitinib achieved clinical remission with few serious adverse events. However, half of patients lost response with de-escalation, which was only partially recaptured with increasing the maintenance dose. Those with negative prognostic factors should be counselled about the risks and benefits of continuing high doses of tofacitinib.

Sleeve gastrectomy facilitates weight loss and permits cardiac transplantation in patients with severe obesity and a left ventricular assist device (LVAD).

INTRODUCTION: Patients suffering from advanced heart failure may undergo left ventricular assist device (LVAD) placement as a bridge to cardiac transplantation. However, those with a BMI above 35 kg/m2 are generally not considered eligible for transplant due to their elevated cardiac risk. We review our experience with bariatric surgery in this high-risk population to assess its safety and efficacy in reducing BMI to permit cardiac transplantation. METHODS: We retrospectively reviewed all patients on durable LVAD support who underwent sleeve gastrectomy (SG) at Mount Sinai Hospital between August 2018 and December 2022. Electronic medical records were reviewed to analyze patient demographics, surgical details, and outcomes regarding weight loss and heart transplantation. RESULTS: We identified twelve LVAD patients who underwent SG. Three were performed laparoscopically and 9 via robotic approach. Four patients (33.3%) underwent an orthotopic heart transplant (OHTx). Half of these patients were female. For patients who underwent OHTx, mean age at LVAD placement was 41.0 (R30.6-52.2), at SG was 43.9 (R32.7-55.0) and at OHTx was 45.3 years (R33.3-56.8). Mean BMI increased from 38.8 at LVAD placement to 42.5 prior to SG. Mean time from SG to OHTx was 17.9 months (R6-7-27.5) during which BMI decreased to mean 32.8 at the time of OHTx. At most recent follow-up, mean BMI was 31.9. All patients were anticoagulated prior to surgery; one required return to the operating room on post-operative day 1 after SG for bleeding and one was re-admitted on post-operative day 7 for hematochezia treated conservatively. CONCLUSION: SG is a safe and effective operation in patients with severe obesity and heart failure requiring an LVAD. 66.7% of our cohort achieved target BMI < 35 and 33.3% underwent heart transplantation. Longer term follow-up is needed to clarify full bridge-to-transplant rate and long-term survival outcomes.

The Impact of Age in the Treatment of Non-comorbid Patients with Rectal Cancer: Survival Outcomes from the National Cancer Database.

BACKGROUND: Multimodal therapy has improved survival outcomes for rectal cancer (RC) significantly with an exemption for older patients. We sought to assess whether older non-comorbid patients receive substandard oncological treatment for localized RC referring to the National Comprehensive Cancer Network (NCCN) guidelines and whether it affects survival outcomes. METHODS: This is a retrospective study using patient data from the National Cancer Data Base (NCDB) for histologically confirmed RC from 2002 to 2014. Non-comorbid patients between ≥50 and ≤85 years and defined treatment for localized RC were included and assigned to a younger (<75 years) and an older group (≥75 years). Treatment approaches and their impact on relative survival (RS) were analyzed using loess regression models and compared between both groups. Furthermore, mediation analysis was performed to measure the independent relative effect on age and other variables on RS. Data were assessed using the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist. RESULTS: Of 59,769 included patients, 48,389 (81.0%) were assigned to the younger group (<75 years). Oncologic resection was performed in 79.6% of the younger patients compared to 67.2% of the older patients (p < 0.001). Chemotherapy (74.3% vs. 56.1%) and radiotherapy (72.0% vs. 58.1%) were provided less often in older patients, respectively (p < 0.001). Increasing age was associated with enhanced 30- and 90-day mortality with 0.6% and 1.1% in the younger and 2.0% and 4.1% in the elderly group (p < 0.001) and worse RS rates [multivariable adjusted HR: 1.93 (95% CI 1.87-2.00), p < 0.001]. Adherence to standard oncological therapy resulted in a significant increase in 5-year RS (multivariable adjusted HR: 0.80 (95% CI 0.74-0.86), p < 0.001). Mediation analysis revealed that RS was mainly affected by age itself (84%) rather than the choice of therapy. CONCLUSIONS: The likelihood to receive substandard oncological therapy increases in the older population and negatively affects RS. Since age itself has a major impact on RS, better patient selection should be performed to identify those that are potentially eligible for standard oncological care regardless of their age.

Pilus proteins from Streptococcus pyogenes stimulate innate immune responses through Toll-like receptor 2.

The group A Streptococcus (GAS) pilus is a long, flexible, hair-like structure anchored to the cell surface that facilitates the adherence of GAS to host cells, thus playing a critical role in initiating infections. Because of its important role in GAS virulence, the pilus has become an attractive target for vaccine development. While current research mainly focuses on pilus function and its potential as a vaccine component, there is a lack of knowledge on how the host immune system recognizes and responds to this abundant surface structure. Here we show that both assembled GAS pili and individual pilus proteins induce a potent release of the proinflammatory cytokines tumor necrosis factor and interleukin-8. We further show that the surface-exposed backbone pilin and ancillary pilin 1 subunits are Toll-like receptor 2 (TLR2) agonists. Using reporter cell lines coexpressing human TLR2 in combination with either TLR1 or TLR6, we determined that activation was mediated by the TLR2/TLR6 heterodimer. Finally, we used solid-phase and flow cytometry binding assays to illustrate a direct interaction between the pilus subunits and TLR2. These results provide further support for the suitability of the pilus as a vaccine component and opens potential avenues for using GAS pili as an adjuvant or immune-modulation agent.

Insufficient weight loss after banded vs. non-banded primary gastric bypass surgery: insights from an observational 5 year follow-up study.

BACKGROUND: While Roux-en-Y gastric bypass (RYGB) is effective in achieving weight loss and improving obesity-related co-morbidities, insufficient weight loss in the long-term can occur. The goal was to assess whether banded vs. non-banded RYGB reduces the risk of insufficient weight loss at 5-year follow-up. METHODS: This is a retrospective single-center cohort study from Switzerland. We assessed the 5-year metabolic trajectories in terms of body weight, body mass index, glucose control, lipid profile and blood pressure of two surgical cohorts undergoing identical RYGB procedures with or without banding using a uniform 6.5 cm silastic Fobi band. Insufficient weight loss was defined as < 50% excess weight loss (EWL) at 5 years. RESULTS: A total of 55 patients receiving banded (Fobi) and 55 patients receiving non-banded (non-Fobi) RYGB were included in the analysis. 5-year follow-up was 91% for both groups. Percentage of EWL at 5 years was 78.11 ± 26.1% and 73.5 ± 27%.3 for the Fobi vs. non-Fobi group (p = 0.368), respectively. Insufficient weight loss (defined as < 50%EWL) at 5 years or last follow-up was significantly higher in the non-Fobi group compared to the Fobi group (19/55 vs. 9/55, respectively, OR = 2.639 (95% CI 1.066, 6.531), p = 0.036). Surrogate markers for cardiometabolic outcomes consistently improved over time, without differences between the groups. During the follow-up period, Fobi-removal was necessary in nine patients (16.3%). CONCLUSION: Banded-RYGB lowered the odds of insufficient weight loss at 5 years follow-up by approximately 62%. Further research is needed to explore the effect of restriction on eating behaviour and neuroendocrine responses after RYGB.

Prevalence and Severity of Burn Scars in Rural Mozambique.

BACKGROUND: Burn injuries are common in low- and middle-income countries (LMICs) and their associated disability is tragic. This study is the first to explore burn scars in rural communities in Mozambique. This work also validated an innovate burn assessment tool, the Morphological African Scar Contractures Classification (MASCC), used to determine surgical need. METHODS: Using a stratified, population-weighted survey, the team interviewed randomly selected households from September 2012 to June 2013. Three rural districts (Chókwè, Nhamatanda, and Ribáuè) were selected to represent the southern, central and northern regions of the country. Injuries were recorded, documented with photographs, and approach to care was gathered. A panel of residents and surgeons reviewed the burn scar images using both the Vancouver Scar Scale and the MASCC, a validated visual scale that categorizes patients into four categories corresponding to levels of surgical intervention. RESULTS: Of the 6104 survey participants, 6% (n = 370) reported one or more burn injuries. Burn injuries were more common in females (57%) and most often occurred on the extremities. Individuals less than 25 years old had a significantly higher odds of reporting a burn scar compared to people older than 45 years. Based on the MASCC, 12% (n = 42) would benefit from surgery to treat contractures. CONCLUSION: Untreated burn injuries are prevalent in rural Mozambique. Our study reveals a lack of access to surgical care in rural communities and demonstrates how the MASCC scale can be used to extend the reach of surgical assessment beyond the hospital through community health workers.

Intranasal immunization with Ag85B peptide 25 displayed on Lactococcus lactis using the PilVax platform induces antigen-specific B- and T-cell responses.

Mycobacterium tuberculosis (Mtb) remains a global epidemic despite the widespread use of Bacillus Calmette-Guérin (BCG). Consequently, novel vaccines are required to facilitate a reduction in Mtb morbidity and mortality. PilVax is a peptide delivery strategy for the generation of highly specific mucosal immune responses and is based on the food-grade bacterium Lactococcus lactis that is used to express selected peptides engineered within the Streptococcus pyogenes M1T1 pilus, allowing for peptide amplification, stabilization and enhanced immunogenicity. In the present study, the dominant T-cell epitope from the Mtb protein Ag85B was genetically engineered into the pilus backbone subunit and expressed on the surface of L. lactis. Western blot and flow cytometry confirmed formation of pilus containing the peptide DNA sequence. B-cell responses in intranasally vaccinated mice were analyzed by ELISA while T-cell responses were analyzed by flow cytometry. Serum titers of peptide-specific immunoglobulin (Ig) G and IgA were detected, confirming that vaccination produced antibodies against the cognate peptide. Peptide-specific IgA was also detected across several mucosal sites sampled. Peptide-specific CD4+ T cells were detected at levels similar to those of mice immunized with BCG. PilVax immunization resulted in an unexpected increase in the numbers of CD3+ CD4- CD8- [double negative (DN)] T cells in the lungs of vaccinated mice. Analysis of cytokine production following stimulation with the cognate peptide showed the major cytokine producing cells to be CD4+ T cells and DN T cells. This study provides insight into the antibody and peptide-specific cellular immune responses generated by PilVax vaccination and demonstrates the suitability of this vaccine for conducting a protection study.

Speech and Audiology Outcomes After Single-Stage Versus Early 2-Stage Cleft Palate Repair.

PURPOSE: The timing and management of patients with cleft palates have been controversial. Early soft palate closure at the time of cleft lip repair followed by hard palate closure at a second stage has been hypothesized to improve speech and audiology outcomes. This study compares cleft palate patients who have undergone single-stage versus 2-stage cleft palate repairs and the outcomes on speech and hearing. METHODS: A retrospective chart review identified patients with diagnosis of cleft lip with complete cleft palate who underwent either single or 2-stage repair from 2006 to 2012. Data collected included age at each surgery, necessity of further speech surgery for velopharyngeal insufficiency, frequency of tympanostomy tube placement, presence of hearing loss, and speech assessment data graded per the validated Americleft speech scale. RESULTS: A total of 84 patients were identified and subdivided into groups of single-stage and 2-stage repair. The mean age at the time of single-stage palate repair was 13.3 months. For the 2-stage group, the mean ages were 4.2 and 11.8 months for the soft palate and hard palate repairs, respectively. Comparing the single-stage versus 2-stage palate repairs, there was no significant difference in all speech parameters including hypernasality, hyponasality, nasal air emission, articulation, expressive language, receptive language, speech intelligibility, and speech acceptability for both unilateral and bilateral cleft lip/palate patients. Two-stage repair was associated with increased number of tympanostomy tube placement compared with single-stage repair (relative risk, 1.74; P = 0.009), and the first set of tubes was performed at a statistically significantly younger age, 4.5 months in the 2-stage repair compared with 16.9 months in the single-stage (P = 0.012) with 87.5% performed with first stage of repair. However, there was no difference in the types, degrees of hearing loss, or the presence of at least mild conductive hearing loss at latest follow-up audiograms between the groups. CONCLUSIONS: There was no significant benefit with respect to speech or hearing outcomes between single-stage and 2-stage cleft palate repairs. This advocates for surgeon and family preference in the timing of cleft palate repair.

Is There a Role for Surgery in Patients with Neuroendocrine Tumors of the Esophagus? A Contemporary View from the NCDB.

BACKGROUND: Esophageal neuroendocrine tumors (eNETs) are exceedingly rare, aggressive and have a poor prognosis. Treatment guidelines are ill-defined and mainly based on evidence from case reports and analogous experiences drawn from similar disease sites. METHODS: The NCDB was reviewed for histologically confirmed stage I-III, primary eNETs from 2006 to 2014. Patients were grouped into whether or not they underwent primary tumor resection. Univariate, multivariable, and full bipartite propensity score (PS) adjusted Cox regression analyses were used to assess overall and relative survival differences. RESULTS: A total of 250 patients were identified. Mean age was 65.0 (standard deviation [SD] 11.9) years, and 174 (69.6%) patients were male. Most patients had stage III disease (n = 136, 54.4%), and the most common type of NET was small cell eNET (n = 111, 44.4%). Chemotherapy was used in 186 (74.4%), radiation therapy in 178 (71.2%), and oncological resection was performed in 69 (27.6%) patients. Crude 2-year survival rates were higher in the operated (57.3%) compared with the nonoperated group (35.2%; p < 0.001). The survival benefit held true after multivariable adjustment (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.32-0.69, p < 0.001). After full bipartite PS adjustment analysis, survival was longer for patients who received a surgical resection compared with those who did not (HR 0.48, 95% CI 0.31-0.75, p = 0.003) with a corresponding 2-year overall survival rate of 63.3% (95% CI 52.0-77.2) versus 38.8% (95% CI 30.9-48.8), respectively. CONCLUSIONS: Multimodal treatment that includes surgery is associated with better overall survival for eNETs. Additional research is needed to more definitively identify patients who benefit from esophagectomy and to establish an appropriate treatment algorithm.

Short-term outcomes of endoscopic gastro-jejunal revisions for treatment of dumping syndrome after Roux-En-Y gastric bypass.

BACKGROUND: Dumping syndrome is a known long-term complication of Roux-en-Y gastric bypass (RYGB). Most cases can be avoided with dietary and lifestyle changes. Severe dumping is characterized by multiple daily episodes with significant impact on quality-of-life. As dumping correlates with rapid pouch emptying through a dilated gastro-jejunal anastomosis (GJA), the aim was to assess endoscopic gastro-jejunal revisions (EGR) regarding feasibility, safety, and outcome. METHODS: From January 2016 to August 2018, we reviewed the electronic records of all patients with dumping syndrome undergoing EGR with the Apollo OverStitch suturing device (Apollo Endosurgery, Austin, Texas, USA). Demographics, procedure details, and outcome variables were recorded. Sigstad questionnaire was administered before and after surgery to assess symptomatic response. RESULTS: There were 40 patients (M:F = 13:27) treated with EGR for dumping. Mean procedure time was 18.5 min (12-41) with a median number of 1 suture (range 1-3) used. Mean anastomotic diameter was 22.6 mm (R 18-35) at the beginning and 6.2 mm (R 4-13) at the end of the procedure, with 100% technical success in narrowing the GJA. There were no intra-operative or 30-day complications. Repeat EGR was required in 9 patients (22.5%) for persistent/recurrent dumping. Two patients (5%) required a laparoscopic pouch revision. For patients with minimum 1-month follow-up who were treated only endoscopically, 33/37 (89.2%) had improved or resolved symptoms during the follow-up period. Mean follow-up time was 12.5 months (R1-33.8). Survey responses were available for 25/34 (73.5%) patients. Mean Sigstad score decreased from 13.9 (R 0-28) pre-operatively to 8.6 (R 0-28) after EGR. CONCLUSION: EGR of the dilated GJA is a highly effective treatment option for dumping syndrome after RYGB. Due to its endoluminal approach, it is a feasible and safe procedure, and effective for immediate symptom resolution in most patients. In some patients, repeat narrowing of the anastomosis is necessary for the maintenance of symptom resolution.

No Difference in Survival between Neo-Adjuvant Chemotherapy and Neo-Adjuvant Chemoradiation Therapy in Gastric Cardia Cancer Patients: A Contemporary View from the National Cancer Database.

INTRODUCTION: Both neo-adjuvant chemoradiation therapy (NACRT) and neo-adjuvant chemotherapy (NAC), in addition to surgical resection of gastric cardia cancer, improves survival outcomes. We assessed whether NACRT or NAC had superior overall survival (OS) and relative survival (RS) outcomes using the National Cancer Database (NCDB). METHODS: The NCDB from 2006 to 2014 was reviewed to identify non-metastatic adult gastric cardia cancer patients who underwent surgical resection and received NACRT or NAC. Advanced statistical models were applied to assess survival outcomes. RESULTS: Of the 5,371 patients included, 4,520 (84.2%) were male, the mean age was 61.2 years (SD 10.0), 4,229 (78.7%) underwent NACRT, and 1,142 (21.3%) underwent NAC. NACRT patients more often had an R0 resection compared to NAC (91.4 vs. 86.6%, p < 0.001, respectively). Univariate 5-year OS rates were 40.0% (95% CI 38.2-41.8) for NACRT and 40.1% (37.0-43.6) for NAC (p = 0.302). No differences in OS for NAC vs. NACRT were found after multivariable analysis (hazard ratio [HR] 0.95, 95% CI 0.86-1.05, p = 0.290). There were no survival differences after stepwise, propensity score, RS analyses, nor after near-far-matching (HR 0.94, 95% CI 0.82-1.07, p = 0.332). CONCLUSIONS: NAC or NACRT yield the same survival outcome for patients with resectable gastric cardia cancer. These data support the need for randomized controlled trials comparing the 2 regimens head-to-head.

Role of lymphadenectomy, adjuvant chemotherapy, and treatment at high-volume centers in patients with resected pancreatic cancer-a distinct view on lymph node yield.

PURPOSE: While the importance of lymphadenectomy is well-established for patients with resectable pancreatic cancer, its direct impact on survival in relation to other predictive factors is still ill-defined. METHODS: The National Cancer Data Base 2006-2015 was queried for patients with resected pancreatic adenocarcinoma (stage IA-IIB). Patients were dichotomized into the following two groups, those with 1-14 resected lymph nodes and those with ≥ 15. Optimal number of resected lymph nodes and the effect of lymphadenectomy on survival were assessed using various statistical modeling techniques. Mediation analysis was performed to differentiate the direct and indirect effect of lymph node resection on survival. RESULTS: A total of 21,912 patients were included; median age was 66 years (IQR 59-73), 48.9% were female. Median number of resected lymph nodes was 15 (IQR 10-22), 10,163 (46.4%) had 1-14 and 11,749 (53.6%) had ≥ 15 lymph nodes retrieved. Lymph node positivity increased by 4.1% per lymph node up to eight examined lymph nodes, and by 0.6% per lymph node above eight. Five-year overall survival was 17.9%. Overall survival was better in the ≥ 15 lymph node group (adjusted HR 0.91, CI 0.88-0.95, p < 0.001). On a continuous scale, survival improved with increasing LNs collected. Patients who underwent adjuvant chemotherapy and were treated at high-volume centers had improved overall survival compared with their counterparts (adjusted HR 0.59, CI 0.57-0.62, p < 0.001; adjusted HR 0.86, CI 0.83-0.89, p < 0.001, respectively). Mediation analysis revealed that lymphadenectomy had only 18% direct effect on improved overall survival, while 82% of its effect were mediated by other factors like treatment at high-volume hospitals and adjuvant chemotherapy. DISCUSSION: While higher number of resected lymph nodes increases lymph node positivity and is associated with better overall survival, most of the observed survival benefit is mediated by chemotherapy and treatment at high-volume centers.

Adherence to surgical and oncologic standards improves survival in breast cancer patients.

BACKGROUND: Adherence to evidence-based standards can lead to improved outcomes for patients with breast cancer. However, adherence rates to standards and their effects on patient outcomes are unknown. OBJECTIVES: To examine adherence rates to standards compiled by the American College of Surgeons Clinical Research Program and its effects on patient outcomes. METHODS: Using the National Cancer Database (2004-2015), we identified cohorts of breast cancer patients: clinical T1N0M0 under age of 70 (cT1), clinical T2N0M0 or T3N0M0 (cT2/3), and clinical M0 and pathologic N2 or N3 (pN2/3). Standards included negative margins, any adjuvant therapy, and two or more lymph nodes (LNs) examined (for cT1 or cT2/3 patients) or more than 10 LNs examined (for pN2/3 patients). We performed Kaplan-Meier and Cox proportional hazards analysis. RESULTS: We identified 318 853 (65.0%) cT1, 164 593 (67.3%) cT2/3, and 77 626 (67.7%) pN2/3 patients who met the standards. More than 90% of patients had negative margins and adjuvant therapy, but less than 80% met LN standards. The median overall survival (OS) was significantly longer for patients who met the standards. Individual components of the standards were predictors of improved OS. CONCLUSIONS: One-third of patients did not meet the evidence-based standards in their treatment for breast cancer. Efforts to improve the knowledge of and adherence to these standards should be emphasized.

ASBRS Great Debate: Sentinel Node Biopsy in Patients Over 70 Years of Age.

INTRODUCTION: Controversy over the need for sentinel node biopsy (SNB) continues to exist for the optimal treatment of breast cancer in patients ≥ 70 years of age, especially in those with lower-risk disease. Clinicians must balance competing risks to give the best individualized care. METHODS: The American Society of Breast Surgeons (ASBrS) conducted a debate discussing the pros and cons of routinely performing SNB in this age group. Small, randomized studies have been conducted that show no overall survival benefit to axillary intervention (either axillary dissection or SNB) in patients with clinically T1N0 estrogen receptor (ER)- and progesterone receptor (PR)-positive, HER2/neu-negative tumors. There may be a small local recurrence benefit to axillary staging in patients who do not undergo radiation. Alternatively, axillary ultrasound, which carries a low false-negative rate for heavy disease burden, can be used to select patients who can avoid SNB. CONCLUSION: Surgeons must continue to individualize care of breast cancer patients over 70 years of age in whom competing comorbidities may dictate care. No randomized clinical trials (RCTs) have found a survival benefit to axillary staging in this low-risk population. However, in healthy patients, axillary staging may improve local control, provide prognostic information, and help guide decisions regarding adjuvant therapy such as chemotherapy and radiation. Ongoing RCTs are evaluating the benefit of SNB in patients with a negative axillary ultrasound. Until those results are available, clinicians and patients must balance the risk and benefits to determine if SNB adds significant value to their overall care.

Novel targeted drug delivery systems to minimize systemic immunosuppression in vascularized composite allotransplantation.

PURPOSE OF REVIEW: The long-term adverse effects of immunosuppressive treatment, the high rate of acute rejection and the development of chronic rejection are the main factors preventing a wider clinical application of vascularized composite allotransplantation (VCA). Targeted immunosuppression using innovative drug delivery systems (DDS) may help to overcome these hurdles, increasing therapeutic efficacy while reducing systemic toxicity. This review provides a summary of the recently developed strategies for targeted delivery of immunosuppressive drugs in VCA. RECENT FINDINGS: Currently, several innovative strategies for targeted immunosuppression have been designed based on the anatomy and function of the target organ. Site-specific DDS have been developed both for directly accessible organs (i.e. skin, eye and lung) and internal organs (i.e. lymph nodes, liver, nervous system, etc.). In preclinical models, DDS designed for sustained, 'on demand,' or 'on cue' drug release has been shown to promote VCA survival while reducing systemic toxicity. These findings suggest that targeted delivery could increase patient compliance and potentially decrease toxicity in VCA recipients. SUMMARY: Targeted immunosuppression in VCA represents a promising approach for improving patient compliance and graft survival while reducing off-target toxicity, intensity and frequency of acute rejection episodes and risk of chronic rejection. VIDEO ABSTRACT.

High rate of positive lymph nodes in T1a gallbladder cancer does not translate to decreased survival: a population-based, propensity score adjusted analysis.

BACKGROUND: Current consensus guidelines suggest that gallbladder cancer (GBC) patients with resected T1a disease can be observed while patients with T1b or greater lesions should undergo lymphadenectomy (LNE). The primary aim of this study was to critically explore the impact of LNE in early-stage GBC on overall survival (OS) on a population-based level. METHOD: The 2004-2014 National Cancer Database was reviewed to identify non-metastatic GBC patients with T1a, T1b, or T2 disease and grouped whether a dedicated LNE was performed. OS and relative survival were assessed using Cox proportional hazard regression analyses before and after propensity score adjustments. RESULTS: 4015 patients were included, 246 (6%) had T1a, 654 (16%) T1b, and 3115 (78%) T2 GBC. The rate of positive lymph nodes was 13%, 12%, and 40% for T1a, T1b, and T2 tumors, respectively. Even after propensity score adjustment, no OS benefit was found if LNE was performed for T1a disease (HR:0.63, 95%CI:0.35-1.13) while OS was improved for T1b (HR:0.65, 95%CI:0.49-0.87) and T2 tumors (HR:0.65, 95%CI:0.57-0.73). CONCLUSION: Despite a higher rate of nodal positivity among patients with T1a disease compared to previous reports, there was no impact on survival and current treatment guidelines appear appropriate for the management of T1a disease.